The present invention relates to the measurement of the concentration of constituents of interest using radiation, preferably near infrared radiation. More particularly, an improved apparatus has been developed which utilizes a method of measuring the concentration of constituents such as glucose, alcohol, hemoglobin and its variants such as deoxyhemoglobin, myoglobin, and other reduced or substituted forms of hemoglobin or heme-group containing molecules, drugs of abuse or other clinical analytes in a non-invasive manner. Because the apparatus and method do not require a finger puncture to obtain a blood sample, they are particularly suitable for home glucose testing.
With the spread of AIDS, and the associated fear among the public and health care personnel of contracting the disease, development of testing methods that do not require invasive procedures, including the taking of blood samples, has become an important goal. Not only AIDS, but other diseases such as hepatitis may be spread through invasive procedures if adequate precautions are not taken. For example, a recent article, "Nosocomiel transmission of Hepatitis B virus associated with the use of a spring-loaded finger-stick device," New England Journal of Medicine 326 (11), 721-725 (1992), disclosed a hepatitis mini-epidemic in a hospital caused by the improper use of an instrument for taking blood samples. The article describes how the nurses were unintentionally transmitting hepatitis from one patient to another with the sampling device itself. This type of disease transfer is eliminated by non-invasive testing.
Effective management of diabetes has also given rise to the need for non-invasive testing instruments. Many diabetics must measure their blood glucose levels four or more times a day. Instruments currently used for in-home glucose testing require a painful finger prick to obtain a blood sample. Although the price of these instruments has dropped considerably, such testing requires the use of disposable materials that can be cumulatively costly. Further, the discomfort, inconvenience, and health risks associated with frequent puncture bleeding are considerable.
Accordingly, a number of groups have recently tried to make non-invasive instruments for measuring the concentration of various analytes, particularly blood glucose. Much of the recent development work in non-invasive testing has been exploring the use of the near infrared spectral region (700-2500 nm). This region contains the third overtones of the glucose spectrum and its use eliminates many of the interference bands that cause potential problems for detection. However, substantially all of this work has been carried out using classic spectrophotometric methods. These methods use a set of narrow wavelength sources and a broad wavelength response detector (Rosenthal), a broad wavelength source and narrow wavelength response detectors (Sandia),or scanning spectrophotometers which scan wavelength by wavelength across a broad spectrum. The data obtained with these methods are spectra which require substantial data processing to eliminate (or minimize) the background. Accordingly, the relevant papers are replete with data analysis techniques utilized in an attempt to extract the pertinent information. Examples of this type of testing include the work by Clarke, see U.S. Pat. No. 5,054,487, and the work by Rosenthal et al., see, e.g., U.S. Pat. No. 5,028,787. Although the Clarke work uses reflectance spectra and the Rosenthal work uses primarily transmission spectra, both rely on obtaining near infrared spectrophotometric data.
One problem with all such methods is that spectrophotometers were conceived primarily for accurate wavelength-by-wavelength measurement of spectral intensities. Where, as in non-invasive measurement of the concentration of glucose and other clinical materials, the analyte of interest has weak broadband spectral features and is present in a mixture containing other substances with substantially overlapping broadband spectral structure, use of classical spectrophotometric methods employ substantial, and ultimately unsatisfactory, data analysis in an attempt to extract the desired concentration from a background of interfering signals. One basic principal of all measurement is, however, that the measurement step determines the information content of the data, and that computation or transformation adds no new information. In other words, no amount of analysis can make up for the fact that the distinguishing features of the spectra of the analytes of interest are not the sharp spectral peaks of classical spectrophotometry but rather are broad and shallow structures. The analyte is identifiable not by the location of its spectral peaks, but by the global structure of its intensity versus wavelength structure. Since spectrophotometers are not designed to generate this kind of information, they are ill-suited for measurements of this type.
The spectra of the analytes of interest, consisting of a few weak low resolution features, with overlapping backgrounds, are reminiscent of the spectra of reflected, emitted, or transmitted light from colored objects in the visible. The human visual system, while an incompetent spectrophotometer, is superb at the subtlest color discrimination and identification, even under greatly varying illumination conditions. Therefore, the present invention draws on an analogy with the discrimination of colored objects by the eye, rather than classic spectrophotometric measurements, to obtain data. Because of its greater penetration of tissue, the preferred spectral region for testing is the infrared.
Many related but distinct approaches are possible in developing an apparatus and a method for measuring the concentration of an analyte of interest by exploiting the analogy to color perception in the visible. The primary approach is to illuminate the object with broadband radiation, the analog of white light in the visible, and to use a series of spectrally overlapping filters to detect the reflected, emitted or transmitted radiation to determine the object's relative "color." This approach is disclosed in U.S. patent application Ser. No. 914,265, the disclosure of which is incorporated herein by reference. Similarly, U.S. patent application Ser. No. 130,257, the disclosure of which is also incorporated herein by reference, concerns a number of modifications and improvements on the basic method and apparatus disclosed in application Ser. No. 914,265. The present application concerns further modifications and improvement on the methods and apparatus described therein to obtain even better data. In fact, many of these methods are useful even in classic spectrophotometric systems.
While visual perception is very complex and not completely understood, significant progress has been made recently. For example, one recent article, "Color categorization and color constancy in a neural network model of V4," Biological Cybernetics 65,293-303 (1991) describes the simulation of neurons which mix the signals from the three types of visual cones to mimic the ability of the retina and region V4 of the cerebral cortex to respond preferentially to particular colored stimuli, and to disregard changes in the illuminant in the identification of the color of objects in a multi-colored scene. The latter feature is called color constancy. A related article, "A Real-Time Neural System for Color Constancy," IEEE Transactions on Neural Networks, Vol. 2, No. 2, March 1991, describes the hardware implementation of a number of color constancy algorithms based on Land's Retinex theory to improve the ability of a TV system to produce true-color images under varying illumination conditions, the disclosure of which is incorporated herein by reference. One feature of the models which leads to the improvements is the mixing of spatial variations between a given cone and other adjacent ones in its so-called surround region.
One approach for relating the concentration of an analyte to absorption or reflection in the infrared is to obtain and process the raw data as closely as possible to the known aspects of color perception, utilizing a succession of steps or processing levels. Each step provides a useful product and succeeding steps represent products of greater capability.
The first step to achieve accurate information is the simple analog of a colorimetry approach. Colorimetry is numerical color communication in which three dimensions are used to describe the color. It is the trivalent nature of color vision that permits color to be specified in a three dimensional space.
There presently are several such three dimensional colorimetry spaces in use. One of these spaces is the CIE 1931 (x, y)-chromaticity diagram, shown in FIG. 1b, which shows hue and saturation values. Luminosity, the third dimension, is not shown in FIG. 1b but would be in a Z-direction. FIG. 1a shows the standard observed spectral responses used to generate FIG. 1b.
Another colorimetric space, described in terms of hue, chroma, and value, is shown in FIG. 2. This solid can be described as the three numerical values which can specify any perceived color.
It is important to note that although it is convenient to describe color in terms of colorimetry, this is not true color perception which is much more complex. However, colorimetry is useful for color matching under specific conditions. An analog of colorimetry, particularly one in the infrared region, would show similar usefulness in determining analyte concentration.
There are commercially available colorimeters in the visible for measuring tristimulus values in terms of luminosity, hue and saturation, yielding numerical values such as are illustrated by FIG. 1. Briefly, these colorimeters use three detectors, with each detector input being filtered with a different filter function. Each of the filter functions and detector responses are chosen to be similar to the three absorption spectra of the pigments of the three color receptive cones of the human retina. It appears that no one other than the present inventors have previously used, or even considered the use, of an analog of color perception for wavelength expanded colorimetry for concentration measurements or even applied the method of colorimetry to infrared measurements as described herein.
In addition to non-invasive blood measurements for constituents like glucose, the system could replace present pulse oximeters. Non-invasive measurement of arterial oxygen saturation by pulse oximetry is widely acknowledged to be one of the most important technological advances in clinical patient monitoring. Pulse oximeters measure differences in the visible and near infrared absorption spectra of fully oxygenated and reduced hemoglobin in arterial blood. Unlike clinical blood gas analyzers, which require a sample of blood from the patient and can only provide intermittent measurement of patient oxygenation, pulse oximetry provide continuous, and instantaneous, measurement of blood oxygen levels.
However, current commercial oximeters, and their algorithms are inaccurate under conditions of low pulse pressure and/or low oxygen saturation. These severe conditions are observed in the normal unborn fetus or where the features of interest are broad. Unlike the transmission sampling of the commercial oximeters, space limitations associated with the fetus require that the spectral data be obtained by reflectance sampling. It has been suggested that a new analysis technique using multivariate calibration methods can improve the precision, accuracy and reliability of quantitative spectral analysis. Even these techniques are limited by the type of input data.
The apparatus and methods of U.S. patent application Ser. No. 914,265 solves this problem by providing infrared analogs of colorimetry. While the data provided is better than that from spectrophotometers, signal-to-background can always be improved, thereby providing even greater sensitivity.
Further, one problem common to all optical non-invasive test systems is improper readings due to stray or extraneous radiation. A system which eliminates or minimizes this problem has particular advantageous properties for the noncontrolled setting such as home glucose monitoring.
Accordingly, an object of the invention is to provide an apparatus which provides an improved measure of the concentration of a constituent of interest in a sample using the infrared analog of colorimetry.
Another object of the invention is to provide an improved method of accurately, inexpensively, and quickly measuring the concentration of clinical analytes in a non-invasive manner using an analog of colorimetric analysis.
A further object of the invention is to provide an improved apparatus for and a method of non-invasive concentration measurements using the analog of colorimetry that allows for convenient sample insertion and removal while minimizing responsive to radiation from extraneous sources.
A still further object of the invention is to provide an apparatus for and a method of non-invasive determinations of the concentration of an analyte of interest in a mammalian bloodstream with an improved signal-to-background level.
A still other object of the invention is to use a scanning interferometer to provide the illuminating and coding source in the method of the invention.
These and other objects and features will be apparent from the description and the accompanying drawing.